DNA Repair

DNA repair refers to the mechanisms by which a cell maintains the integrity of its genetic code. This integrity not only ensures the survival of a species, which requires that parental DNA be inherited as faithfully as possible by the offspring, but it also preserves the health of an individual. Mutations in the genetic code can lead to cancer and other genetic diseases.

Successful DNA replication requires that the two purine bases, adenine and guanine, pair faithfully with their pyrimidine counterparts, thymine and cytosine. There are three types of damage that can prevent correct base pairing: spontaneous mutations, replication errors, and chemical modification. Spontaneous mutations occur when DNA bases react with their environment, as when water hydrolyzes a base and changes its structure, causing it to pair with the wrong base. Replication errors are minimized when the DNA replication machinery “proofreads” its own synthesis, but sometimes the mismatched bases escape proofreading. Chemical agents modify bases and interfere with DNA replication. Nitrosamines, found in beer and pickled food products, aklylate bases and the DNA backbone. Oxidizing agents or ionizing radiation create free radicals in the cell that oxidize bases, especially guanine. Ultraviolet (UV) rays fuse adjacent pyrimidines, preventing DNA replication. Ionizing radiation or drugs such as bleomycin can also block replication, by creating double-stranded breaks in the DNA. Base analogs or intercalating agents can cause abnormal insertions and deletions in the sequence.

There are three types of repair mechanisms: direct reversal of the damage, excision repair, and recombination repair. Direct reversal repair is specific to the damage. For example, in a process called photoreactivation, pyrimidine bases fused by UV light are separated by DNA photolyase. For direct reversal of akylation events, a DNA methyltransferase detects and removes the alkyl group. Excision repair can be specific or nonspecific. In base excision repair, DNA glycolyases specifically identify and remove the mismatched base. In nucleotide excision repair, the repair machinery nonspecifically recognizes distortions in the double helix caused by mismatched bases and excises the distorted region. Recombination repair takes advantage of the fact that mammalian chromosomes come in pairs, and uses the sequence from an undamaged sister chromosome to repair the damaged one.

Often when DNA is damaged, the cell chooses to replicate over the lesion instead of waiting for repair (translesion synthesis). Although this may lead to mutations, it is preferable to a complete halt in DNA replication, which leads to death. On the other hand, the importance of proper DNA repair is highlighted when repair fails. The oxidation of guanine by free radicals leads to G-T transversion, one of the most common mutations in human cancer.

Hereditary nonpolyposis colorectal cancer results from a mutation in the MSH and MLH proteins, which repair mismatches during replication. Xeroderma pigmentosum (XP) is another condition that results from failed DNA repair. Patients with XP are highly sensitive to light, exhibit premature skin aging and are prone to malignant skin tumors, all because the XP proteins, which mediate nucleotide excision repair, can no longer function.